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PubMed · 42708327

Evaluating the pathogenic significance of unique chromosomal variants in craniosynostosis using patient-derived induced pluripotent stem cells and mouse modelling.

Dagmara Korona·Akiko Soneda Hashimoto·Yang Pei·Eduardo Calpena·Jackie Sloane-Stanley·Simone G Riva·Ron Schwessinger·Francesca Forzano·Satyan Chintawar·Galbha Duggal·Steven A Wall·Jim R Hughes·Stephen R F Twigg·Andrew O M Wilkie
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Abstract

PURPOSE: Unravelling causal links between unique structural/copy-number variants (SV/CNV) and associated phenotypes is essential for correct genetic counselling. We investigated two families in which patients with craniosynostosis had SV/CNV potentially dysregulating a fibroblast growth factor (FGF)-encoding gene; a 730 kb dup(4)(q21.21) including FGF5; and a complex 568 kb interspersed 13q12.11 duplication, located 841 kb from FGF9. METHODS: We combined bioinformatic predictions of altered topologically-associating domain (TAD) structure, with experimental analysis (RNA- and ATAC- [assay for transposase-accessible chromatin] sequencing) of patient induced pluripotent stem cell lines (iPSCs) differentiated to neural crest (NCC) and osteoprogenitor (OPC) identities. For the dup(4)(q21.21) we generated a mouse bearing an equivalent rearrangement using CRISPR-Cas9 targeting. RESULTS: TAD analysis suggested potential dysregulation of the FGF5/FGF9 gene by bringing it into a novel genomic milieu. The RNA- and ATAC-seq assays demonstrated FGF5/FGF9 upregulation (2.7-18x) and local opening of chromatin, in 3/4 cell lines. For the dup(4)(q21.21), a causal role was supported by the mouse model, whereas interpretation of the 13q12.11 SV is confounded by a co-existing FOXP2 pathogenic variant. CONCLUSION: Patient iPSC-differentiated NCC and OPC lines, combined with TAD-based modelling to generate testable functional hypotheses, provide valuable functional evidence when evaluating causation of unique SV/CNV in craniosynostosis.

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Dagmara Korona, Akiko Soneda Hashimoto, Yang Pei, Eduardo Calpena, Jackie Sloane-Stanley, Simone G Riva, Ron Schwessinger, Francesca Forzano, Satyan Chintawar, Galbha Duggal, Steven A Wall, Jim R Hughes, Stephen R F Twigg, Andrew O M Wilkie. 2026-09-08. Evaluating the pathogenic significance of unique chromosomal variants in craniosynostosis using patient-derived induced pluripotent stem cells and mouse modelling.. https://doi.org/10.1016/j.gim.2026.102716

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